mdr-tb paper for elective study
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tuberkulosisTRANSCRIPT
ELECTIVE STUDY
MULTI DRUG RESISTANT TUBERCULOSIS
By Brigitta Marcia Budihardja
NIM 1302005172
Supervised by
dr. I Nyoman Semadi, Sp.B, Sp.BTKV
FACULTY OF MEDICINE
UDAYANA UNIVERSITY
2014
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FOREWORD
Praise to God Almighty whose blessings has made the accomplishment of
this paper possible. I want to express my biggest gratitude to my supervisor, dr. I
Nyoman Semadi, Sp.B, Sp.BTKV who has guided me pleasantly in the process of
writing this paper. I also want to thank my fellow students who has helped and
motivated me in the process of writing this paper.
This paper is titled “Drug-resistant Tuberculosis”. This paper is written
through literature review. This paper explains MDR-TB (Multi Drug Resistant
Tuberculosis) as an emerging condition that needs immediate response to prevent
further development of the condition. The aim of this paper is to gain knowledge
about this condition as the result of the writing process. Hopefully, this paper can
be also be used by other fellow students as a source of new knowledge and
information. The benefit of this paper is also to put this problem in the spotlight.
There are still a lot of mistakes and flaws in this paper due to the lack of
experience of the writer. Constructive criticism and suggestions are more than
welcomed in hope of gaining more experience for future writing.
Lastly, I sincerely hope that this paper can be helpful for the readers.
Thank you for reading this papers.
Denpasar, August 23rd 2014
Writer
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CONTENT LIST
Foreword…………………………………………………………………… i
Content List………………………………………………………………... ii
I. INTRODUCTION
1.1 Background……………………………………………………… 1
1.2 Problem Identification…………………………………………... 2
1.3 Aims…………………………………………………………….. 2
1.4 Benefits…………………………………………………………. 2
II. CONTENT
2.1 Definition……………………………………………………….. 3
2.2 Classification…………………………………………………… 4
2.3 Epidemiology…………………………………………………… 4
2.4 Diagnostics……………………………………………………… 5
2.5 Surgical Treatment……………………………………………… 6
III. CONCLUSION
3.1 Conclusion……………………………………………………… 11
3.2 Recommendation………………………………………………… 11
References 12
Appendix 14
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I. INTRODUCTION
1.1 Background
For decades, Tuberculosis (TB) has been a major global health problem. It
has been the top cause of death compared to other treatable infectious diseases.
More than one third of world population has been infected by tuberculosis [1].
Tuberculosis occurs worldwide and it has remained as an important cause of
morbidity and mortality in many countries. World Health Organization (WHO)
reported that there were an estimated 9.4 million new cases of TB and 14.0
million prevalent cases causing death to 1.3 million people in 2009 [2]. In
Indonesia, TB is a huge problem. TB is the number one cause of death among
communicable diseases and also ranked as the top third cause of death in
Indonesia [3].
Lately, multi-drug resistant Tuberculosis (MDR-TB) has emerged as a
new and serious problem resulting from inappropriate treatment of TB. Although
the history of anti-tuberculosis drug resistance is fairly recent, emerging just over
60 years ago [4], the incidence and degree of TB drug resistance are increasing
worldwide [5]. Every year, approximately 500.000 new cases of MDR-TB are
diagnosed [6]. Globally, more than 50,000 cases of XDR-TB emerge every year
as a result of poor management of both drug-susceptible and drug-resistant TB
[2]. World Health Organization has estimated a worldwide prevalence of 150,000
MDR-TB related deaths annually [7]. Out of all TB cases, about 3,6% has turned
into MDR-TB [1]. Mycobacterium tuberculosis’ resistance to antibiotics has
developed as one of the most challenging problems to disease control all around
the world [8].
In reality, MDR-TB is a manmade problem. MDR-TB is generated by
poor clinical practices and also poor control strategies in new TB patients.
Mismanagement of MDR-TB with inconsistent use of second-line drugs may lead
to development of XDR-TB [2].
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1.2 Problem Identification
What is Multi-Drug-Resistant Tuberculosis?
How is the role of surgery as a possible treatment of Multi-Drug-Resistant
Tuberculosis?
1.3 Aims
Aim of this paper is to elaborate multi drug resistant Tuberculosis as an
emerging global health problem. This paper aim to explain this disease and also
present a possible treatment for this condition. The writer hopes that with writing
this paper, a clear general understanding of drug-resistant Tuberculosis can be
gained as a result.
I.4 Benefits
Benefit from this paper is to spread the knowledge and concern for multi drug
resistant Tuberculosis as a public health challenge worldwide. This paper is
expected to put attention to MDR-TB as an important issue that needs special
attention from health workers, especially in countries where Tuberculosis is a big
burden, such as Indonesia. Hopefully, this paper can be used as a way to share
knowledge of drug-resistant Tuberculosis to fellow medical students.
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II. CONTENT
2.1 Definition
Tuberculosis is an infectious
disease that is caused by infection of
Mycobacterium tuberculosis [9].
Compared to any other single microbial
agent, Mycobacterium tuberculosis has
caused more deaths. Mycobacterium
tuberculosis is transmitted from one
person to another by respiratory aerosol.
Its initial site of infection is the lung
[10]. Tuberculosis is a result from tissue
hypersensitivity that leads to granuloma
formation with organization of
lymphocytic predominant cellular
proliferation with Langhan cell giant
cells fibroblasts and capillaries [9].
Tuberculosis, when not properly treated, can lead to drug-resistant TB.
Patients with drug-resistant TB carry strains that are resistant to certain anti-
tuberculosis drugs [4]. Drug resistant TB is a result of inappropriate treatment of
TB, whether due to prescribing error or to patient’s poor compliance with therapy.
There are a lot of factors that contributed in the emergence of MDR-TB. Both
social and medical factors underlie the emergence of multi-drug resistant TB
(MDR-TB) [08]. The main risk factor for the development of resistance among
TB cases is incorrect TB treatment. It is usually linked with irregular drug use,
errors in medical prescription, poor patient obedience with the therapy, and low
quality of TB drugs [8].
Patient’s motivation is also one of the risk factors for MDR-TB. A patient
who is less motivated has 4,2 higher risk to have MDR-TB compared to other
patient who is highly motivated [3]. Some social determinants also contributed as
risk factors for MDR-TB. Unemployment, alcohol abuse, and smoking were
Figure 1. Chest Radiograph showing consolidation in superior portion of upper right lobe, a typical site of Tuberculosis associated pulmonary abnormalities. Adapted from http://web.stanford.edu/group/parasites/ParaSites2006/TB_Diagnosis/Current%20Diagnostic%20Techniques.html
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additional risk factors for resistance for second-line drugs of TB. HIV infection,
age less than 35 years, history of imprisonment are also risk factors for drug-
resistant TB [8]. Public health system also contributed in MDR-TB. The
incompetent utilization of resources, specifically the available treatment
strategies, has led to alarming levels of MDR-TB in many parts of the world.
Most of MDR-TB factors are somehow related to poor functioning of National
Tuberculosis Programs (NTPs), such as the DOTS strategy that has not been
implemented properly [4]. Low number of visit to the Primary Health Center is
also included as one of the risk factors of MDR-TB [1].
MDR-TB is far more difficult to treat compared to drug-susceptible TB.
The drugs used to treat MDR-TB are highly toxic, cost a lot more than the one
used for drug-susceptible TB. Treatment duration is also longer. These treatments
often lead to disappointing outcomes [5]. The treatment is also more complex and
has higher relapse rates and a lower likelihood of treatment success when
compared to drug-susceptible TB [6].
2.2 Classification
Multi-drug resistant Tuberculosis (MDR-TB) indicates bacillary resistance
to at least isoniazid and rifampicin [11]. Isoniazid and rifampicin are the two most
effective first-line drugs for TB. Pre-extensively drug resistant TB (Pre-XDR-TB)
refers to MDR-TB resistant to one of the following; second-line injectable drug or
a fluoroquinolone [6]. Extensively drug-resistant (XDR) TB is MDR-TB with
additional bacillary resistance to any fluoroquinolone and at least one of the three
second-line injectable drugs (SLID), which are kanamycin, amikacin and
capreomycin [11].
2.3 Epidemiology
World Health Organization has estimated a worldwide prevalence of
150,000 MDR-TB related deaths annually [7]. In 2012, the estimated global
burden of MDR-TB was 450,000, including 300,000 incident MDR-TB cases.
This means that the growth of MDR-TB is rapid. But, number of MDR-TB cases
that were reported to the WHO in 2012 was just 94,000 MDR-TB cases, which is
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less than a third of the estimated cases. The gap between number of reported and
estimated cases is caused by limited access to drug-susceptibility testing [8].
MDR-TB is currently under-diagnosed and not treated adequately. Globally, less
than 2% of new cases and 6% of previously treated cases were tested for MDR-
TB. Also, only 16% of MDR-TB cases notified in 2010 were given treatment
[11]. By the end of 2012, 92 countries had reported cases of XDR-TB. Among
MDR-TB cases, the average percentage of XDR-TB cases was 9.6% (95% CI:
8.1%–11%) [8].
2.4 Diagnostics
2.4.1 Signs and symptoms
For tuberculosis in general, signs and symptoms include fever, fatigue,
weight loss, night sweats, and a productive cough [12]. Fever is the most common
symptom of TB. It occurs in approximately 70% of patients with TB. Other
symptoms are pleuritic and nonpleuritic chest pain [9]. The sign and symptoms of
drug-resistant TB are similar to drug-susceptible TB. To correctly diagnose drug-
resistant TB, a laboratory diagnosis is needed.
2.4.2 Laboratory testing
To diagnose drug-resistant TB, culture-based test called drug-
susceptibility testing (DST) is performed. Conventional DST includes the
demonstration of the presence of Mycobacterium tuberculosis growth in the
presence of specific anti tuberculosis drugs. The golden standard of DR-TB is
solid agar methods. But there are also some other alternatives, which are liquid
culture methods. This method has been proved to have equivalent performance
with the solid agar method. But, in many developing countries, access to DST is
very limited due to the lack of laboratory infrastructure.
Another major weakness of culture-based methods is the long delay in
obtaining DST results. It can take several weeks to get the result [6]. One possible
way to reduce the time delay is to use liquid culture. The expected time for MDR-
TB detection can be shorten to 3–5 weeks by using liquid culture [11].
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New nucleic acid amplification tests (NAATs) provided an alternative
with reduced interval between sample acquisition and susceptibility result from
weeks to hours. By providing rapid DST results, this test has the potential to bring
changes to drug resistant TB epidemic in high burden countries. With faster
diagnosis, correct treatment can be started immediately and the treatment can have
better outcomes [6].
2.5 Surgical Treatment
To treat MDR-TB, a few alternatives are available. MDR-TB can be
treated with new drugs, such as bedaquiline or delamanid [11]. One of the
possible alternatives that will be explored in this paper is surgical treatment.
Surgery plays a decisive role in the overall management of MDR-TB. Surgical
treatment for MDR-TB has shown better mortality and morbidity [13].
Tuberculosis
lesions, which are
penetrated poorly by anti
tuberculosis drugs, contain huge amount of Mycobacterium tuberculosis,
harboring actively replicating bacilli. Cavities act as huge reservoirs of
Mycobacterium tuberculosis infection and also as the likely site of the
development of drug resistance. Since the infection site cannot be reached by the
drugs, to cure the disease completely, it is vitally important to resect the cavitary
lesion and damaged lung tissue [13]. The removal of infected area of lungs by
surgery can reduce the overall organism burden in the lung [6]. By removing the
Figure 2. Gross pathology of resected lung lesion.The inside of the cavity shows caseous necrosis.Adapted from [14]
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main area of infection, it may be possible to prevent further disease spread. This
surgical treatment can also allow medical therapy to work better [7]. Resection of
cavitary lesions, or destructive of a lobe or lung, would decrease the bacilli count,
which can improve the efficiency of medical treatment [13]. Surgery should be
done as soon as chemotherapy is felt to be not sufficient to cure the disease.
Delaying surgery and persisting with ineffective chemotherapy may enable
progression of disease, and further promote the development of drug resistance
[6].
One study has explained a case of a 26-year-old patient with XDR-TB
refractory to medical therapy. Drug susceptibility testing (DST) to first-line anti-
TB drugs, utilizing the agar proportion method, was performed. The result from
this test demonstrated resistance to all first-line drugs including rifampin,
isoniazid, pyrazinamide, ethambutol, and streptomycin. Another DST was
performed to test resistance to second-line anti-TB drugs. The result stated that
there were also resistances to ethionamide, kanamycin, capreomycin, ofloxacin.
After a series of treatment regimen, there was no radiological improvement.
Considering the lack of improvement and also high degree of resistance,
physicians who are in charge for this patient felt that it was unlikely that this
patient would be cured with chemotherapy alone and referred the patient for
evaluation for adjunctive surgical therapy. The patient was considered a good
operative candidate, taking into account his young adult age and no co-morbid
illnesses. Surgical resection of the patient’s solitary cavitary lesion was performed
as adjunctive treatment. After the surgery, the patient was continued on the same
anti-TB treatment regimen. The patient was declared cured from TB a year after
the surgery. With combination of surgery and medical therapy, a successful
outcome was achieved [14].
2.5.1 Pre-operative work up
Before the surgery, a chest CT scan should be done to evaluate the extent
of disease. A pulmonary function testing should also be done to guide surgical
resection. Ventilation perfusion scan should be done to ensure adequate
pulmonary reserve to tolerate surgery. Bronchoscopy is needed to rule out
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endobronchial tuberculosis, contralateral disease, and malignancy [14].
Bronchoscopy is also needed to visualize airway [7]. Echocardiogram should be
done to rule out heart failure and pulmonary hypertension. Nutritional assessment
is also needed to ensure patient can tolerate and recover from surgery [14].
2.5.2 Indications for surgery
Surgery for patient with MDR-TB should be considered for patients who
have persistently positive AFB smear or sputum culture despite aggressive
chemotherapy [14]. Adjunctive lung resection may be considered for patients with
MDR-TB if the patients meet a certain criteria. The criteria include a high
probability of failure or relapse with medical therapy alone, sufficiently localized
disease for resection with adequate postoperative cardiopulmonary capacity, and
sufficient drug activity for facilitating postoperative healing of bronchial stump
[11]. The presence of complications of tuberculosis including bronchiectasis,
empyema, and hemoptysis should also be considered as an indication for surgery
[14].
2.5.3 Methods
Figure 3 (left). Chest radiography(A) Preoperative image showing left lower lobe infiltrate (arrows). (B) One month postoperative image, showing clear lung fields.Adapted from [14]Figure 4 (above). Pre-operative CT Scan of the LungCross-sectional view showing 3x5 cm left lung cavitary lesion.Adapted from [14]
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As has been shown by large cohort studies, the best outcomes in MDR-TB
are achieved by the use of fluoroquinolones and adjunctive surgery [13]. The most
common approach for surgical resection was through a muscle sparing
posterolateral thoracotomy [14]. The median approach has also been studied, but
offers limited exposure for left-sided resections [6]. The type of resection was
based on the extent of the pulmonary lesion [7]. The balance of removing all
affected lung and desire to preserve pulmonary function was used to determine
which type of resection was done [14]. The different types of resections
performed included pneumonectomy, lobectomy, segmentectomy, wedge
resection, and some combination of these procedures. Pneumonectomy is a
surgical procedure in which an entire lung is removed. Lobectomy is a surgical
procedure that removes one lobe of the lung, while removal of 2 lobes is called
bilobectomy. A wedge resection is a surgical procedure during which the surgeon
removes a small, wedge-shaped portion of the lung. This procedure can be
performed by minimally-invasive video-assisted thoracoscopic surgery (VATS) or
a thoracotomy (open chest surgery). Segmentectomy is a surgical procedure that
removes a larger portion of the lung lobe than a wedge resection, but does not
remove the whole lobe [16].
2.5.4 Post-Operative Work Ups
Postoperative individualized chemotherapy is required for MDR-TB
patients even after the removal of the most grossly involved lesions, to ensure
long-term cure [15]. Antibiotic therapy is recommended for approximately 2 years
[13]. Postoperatively, the pleural space was routinely drained with a chest tube.
Occasionally, if resection created a large residual space, a thoracoplasty can be
used to reduce the open space to help prevent further complications [14].
2.5.5 Complication
Few complications can occur after surgery in MDR-TB patients. Possible
complications are postoperative intrathoracic bleeding, bronchopleural fistula, and
empyema [15]. Wound complication is also included as one of the possible
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complications, although minor [6]. The most common complication is
bronchopleural fistula [7].
2.5.6 Outcomes
Many studies have reported favorable outcomes of surgery for MDR-TB.
One study has found a significant association between surgical intervention and
successful outcome when compared to non-surgical treatment alone (OR 2.24,
95% CI: 1.68-2.97) [6]. Another study suggested that pulmonary resection is
curative, reported 100% conversion rate and 92,3% cure rate. But, this study also
stated that ways must be found to reduce the morbidity, which was found to be
23% [13]. Another study reported that sputum negativity was achieved in 93% of
patients [15].
Patients with MDR-TB seem to have better outcomes compared to patients
with XDR-TB. One study reported that favorable outcomes were achieved in 82%
patients, including 90% in those with MDR-TB and 67% in XDR-TB patients [7].
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III. CONCLUSION
III.1 Conclusion
Tuberculosis has been a major global health problem for decades. Now,
the problem has grown. Inappropriate treatment of TB has lead to multi-drug
resistant Tuberculosis (MDR-TB). MDR-TB indicates a resistance to at least 2 of
most effective antituberculous drugs, which are isoniazid and rifampicin. A more
extreme type of MDR-TB is called extensively drug-resistant (XDR) TB. Not
only isoniazid and rifampicin, patients with XDR-TB are also resistant to any
fluoroquinolone and at least one of the three second-line injectable drugs. Both
MDR-TB and XDR-TB has shown rapid growth in global population.
One of the challenges in the fight against drug resistant TB is diagnostic
method. Drug-susceptibility testing (DST) is the main diagnostic laboratory
testing for drug resistant TB. However, this method has some weaknesses, such as
the limited access to this test in developing countries and long delay in obtaining
results. Alternatives that offer better diagnostic testing are using liquid culture
instead of solid or using a newly developed nucleic acid amplification test.
MDR-TB can be treated by surgical treatment to remove infected lung
areas. Surgery is done to remove tuberculosis lesions that contain huge amount of
Mycobacterium tuberculosis and cannot be penetrated by the drugs. Resection of
lesions would decrease the bacilli count, which can improve the efficiency of
medical treatment. Many studies have shown a good outcome resulting from
combination of chemotherapy and surgical treatment.
III.2 Recommendation
Drug-resistant Tuberculosis is a serious problem that needs to be put as a
priority. Development in diagnostic methods is really essential to make better
treatment possible. A diagnostic method that is easy to perform, accessible by
many, and able to provide result in short amount of time, is really needed.
Adjunctive surgery for MDR-TB should be considered as a possible
treatment. Studies have shown that surgery can bring good outcomes for patient
with MDR-TB. A good combination of surgery and medication should be
developed further to achieve best treatment regimen for patients with MDR-TB.
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REFERENCES
1. Nofizar D, Nawas A, Burhan E. Identifikasi Faktor Risiko Tuberkulosis
Multidrug Resistant (TB-MDR). Maj Kedokt Indon. 2010 Dec; 60(12);
537-545.
2. Prasad, R. Multidrug and extensively drug‐resistant tuberculosis
management: Evidences and controversies. Lung India. 2012 June; 29(2);
154-159.
3. Dwi Sarwani SR, Nurlaela S, Zahrotul I. Faktor Risiko Multidrug
Resistant Tuberculosis (MDR-TB). KEMAS. 2012 July; 8(1); 60-66.
4. Caminero, JA. Multidrug-resistant tuberculosis: epidemiology, risk factors
and case finding. Int J Tuberc Lung Dis. 2010; 14(4); 382–390.
5. Shim TS, Jo KW. Medical Treatment of Pulmonary Multidrug-Resistant
Tuberculosis. Infect Chemother. 2013 Sept; 45(4); 367-374.
6. Calligaro GL, et al. The medical and surgical treatment of drug-resistant
tuberculosis. J Thorac Dis 2014;6(3):186- 195.
7. Vashakidze S, et al. Favorable Outcomes for Multi- and Extensively Drug
Resistant Tuberculosis Patients Undergoing Surgery. Ann Thorac Surg.
2013 June ; 95(6): 1892–1898.
8. Matteelli A, Roggi A, Carvalho ACC. Extensively drug-resistant
tuberculosis: epidemiology and management. Clinical Epidemiology. 2014
Apr; 6; 111–118.
9. Slaven EM, Stone SC, Lopez FA. Infectious Diseases: Emergency
Department Diagnosis & Management. New York; McGraw-Hill;2007.
10. Levinson, W. Review of Medical Microbiology and Immunology. New
York; Lange; 2004.
11. Chang KC, Yew WW. Management of difficult multidrug-resistant
tuberculosis and extensively drug-resistant tuberculosis: Update 2012.
Respirology. 2013; 18; 8–21.
12. Wilson WR, Sande MA. CURRENT: Diagnosis and Treatment in
Infectious Diseases. New York; Lange Medical Books/McGraw-Hill;
2001.
15
13. Yaldiz S, et al. Surgery Offers High Cure Rates in Multidrug-resistant
Tuberculosis. Ann Thorac Cardiovasc Surg. 2011; 17: 143–147.
14. Kempker RR, et al. Grand Round Calling the Surgeon: The Role of
Surgery in the Treatment of Drug-Resistant Tuberculosis. Lancet Infect
Dis. 2012 February ; 12(2): 157–166.
15. Xie B, et al. Pulmonary resection in the treatment of 43 patients with well-
localized, cavitary pulmonary multidrug-resistant tuberculosis in
Shanghai. Interactive CardioVascular and Thoracic Surgery. 2013; 17;
455-459.
16. Cardiothoracic Surgery [Internet]. Los Angeles; University of Southern
California [cited 2014 Aug 21]. Available from:
http://www.cts.usc.edu/lpg-typesoflungsurgery.html
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